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Behavioral and cognitive effects of docosahexaenoic acid in drug-naïve children with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled clinical trial.
Crippa, A, Tesei, A, Sangiorgio, F, Salandi, A, Trabattoni, S, Grazioli, S, Agostoni, C, Molteni, M, Nobile, M
European child & adolescent psychiatry. 2019;(4):571-583
Abstract
This study aimed to investigate the efficacy of docosahexaenoic acid (DHA) dietary supplementation on behavior and cognition in school-aged, drug-naïve children with attention-deficit/hyperactivity disorder (ADHD). A total of 50 participants with ADHD aged 7 to 14 were enrolled in a 6-month randomized, placebo-controlled clinical trial and received either DHA or placebo. The primary outcome measure was the change in the ADHD rating scale IV Parent Version-Investigator (ADHD-RS-IV) after 4 and 6 months. Secondary outcome measures included Conners Parent Rating Scale-revised, other behavioral rating scales including quality of life and global functioning, and computerized cognitive tasks. Baseline assessment also addressed the blood fatty acids profile. No superiority of DHA supplement to placebo was observed on ADHD-RS-IV, the a priori primary outcome. DHA supplementation showed a significant, nonetheless quite small, effect on children's psychosocial functioning, emotional problems, and focused attention. Neither major nor minor adverse events were reported throughout the trial. This study shows that 6-month DHA supplementation has no beneficial effect on the symptoms of ADHD in school-aged, drug-naïve children with an established diagnosis of ADHD. Nevertheless, the 6 months treatment with supplemental DHA appears to have small positive effects on other behavioral and cognitive difficulties, which, in light of the absence of side-effects, could be reasonably followed up in future intervention studies. ( https://clinicaltrials.gov/ct2/show/NCT01796262 : The Effects of DHA on Attention Deficit and Hyperactivity Disorder (DADA)).
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n-3 Polyunsaturated fatty acids alter benzo[a]pyrene metabolism and genotoxicity in human colon epithelial cell models.
Tylichová, Z, Neča, J, Topinka, J, Milcová, A, Hofmanová, J, Kozubík, A, Machala, M, Vondráček, J
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2019;:374-384
Abstract
Dietary carcinogens, such as benzo[a]pyrene (BaP), are suspected to contribute to colorectal cancer development. n-3 Polyunsaturated fatty acids (PUFAs) decrease colorectal cancer risk in individuals consuming diets rich in PUFAs. Here, we investigated the impact of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid on metabolism and genotoxicity of BaP in human cell models derived from the colon: HT-29 and HCT-116 cell lines. Both PUFAs reduced levels of excreted BaP metabolites, in particular BaP-tetrols and hydroxylated BaP metabolites, as well as formation of DNA adducts in HT-29 and HCT-116 cells. However, EPA appeared to be a more potent inhibitor of formation of some intracellular BaP metabolites, including BaP-7,8-dihydrodiol. EPA also reduced phosphorylation of histone H2AX (Ser139) in HT-29 cells, which indicated that it may reduce further forms of DNA damage, including DNA double strand breaks. Both PUFAs inhibited induction of CYP1 activity in colon cells determined as 7-ethoxyresorufin-O-deethylase (EROD); this was at least partly linked with inhibition of induction of CYP1A1, 1A2 and 1B1 mRNAs. The downregulation and/or inhibition of CYP1 enzymes by PUFAs could thus alter metabolism and reduce genotoxicity of BaP in human colon cells, which might contribute to known chemopreventive effects of PUFAs in colon epithelium.
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International Society for Nutritional Psychiatry Research Practice Guidelines for Omega-3 Fatty Acids in the Treatment of Major Depressive Disorder.
Guu, TW, Mischoulon, D, Sarris, J, Hibbeln, J, McNamara, RK, Hamazaki, K, Freeman, MP, Maes, M, Matsuoka, YJ, Belmaker, RH, et al
Psychotherapy and psychosomatics. 2019;(5):263-273
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Abstract
Major depressive disorder (MDD) is a complex mental illness with unmet therapeutic needs. The antidepressant effects of ω-3 polyunsaturated fatty acids (n-3 PUFAs) have been widely reported. The subcommittee of the International Society for Nutritional Psychiatry Research organized an expert panel and conducted a literature review and a Delphi process to develop a consensus-based practice guideline for clinical use of n-3 PUFAs in MDD. The guideline focuses on 5 thematic areas: general concepts, acute treatment strategy, depression recurrence monitoring and prevention, use in special populations, and potential safety issues. The key practice guidelines contend that: (1) clinicians and other practitioners are advised to conduct a clinical interview to validate clinical diagnoses, physical conditions, and measurement-based psychopathological assessments in the therapeutic settings when recommending n-3 PUFAs in depression treatment; (2) with respect to formulation and dosage, both pure eicosapentaenoic acid (EPA) or an EPA/docosahexaenoic acid (DHA) combination of a ratio higher than 2 (EPA/DHA >2) are considered effective, and the recommended dosages should be 1-2 g of net EPA daily, from either pure EPA or an EPA/DHA (>2:1) formula; (3) the quality of n-3 PUFAs may affect therapeutic activity; and (4) potential adverse effects, such as gastrointestinal and dermatological conditions, should be monitored, as well as obtaining comprehensive metabolic panels. The expert consensus panel has agreed on using n-3 PUFAs in MDD treatment for pregnant women, children, and the elderly, and prevention in high-risk populations. Personalizing the clinical application of n-3 PUFAs in subgroups of MDD with a low Omega-3 Index or high levels of inflammatory markers might be regarded as areas that deserve future research.
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Fatty acids in pregnancy and risk of allergic sensitization and respiratory outcomes in childhood.
Maslova, E, Rifas-Shiman, SL, Oken, E, Platts-Mills, TAE, Gold, DR
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2019;(1):120-122.e3
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Carbohydrate intake attenuates post-exercise plasma levels of cytochrome P450-generated oxylipins.
Nieman, DC, Gillitt, ND, Chen, GY, Zhang, Q, Sakaguchi, CA, Stephan, EH
PloS one. 2019;(3):e0213676
Abstract
INTRODUCTION Oxylipins are bioactive oxidation products derived from n-6 and n-3 polyunsaturated fatty acids (PUFAs) in the linoleic acid and α-linolenic desaturation pathways. PURPOSE This study determined if carbohydrate intake during prolonged and intensive cycling countered post-exercise increases in n-6 and n-3 PUFA-derived oxylipins. METHODS The research design utilized a randomized, crossover, counterbalanced approach with cyclists (N = 20, overnight fasted state, 7:00 am start) who engaged in four 75-km time trials while ingesting two types of bananas (Cavendish, Mini-yellow), a 6% sugar beverage, and water only. Carbohydrate intake was set at 0.2 g/kg every 15 minutes, and blood samples were collected pre-exercise and 0 h-, 0.75 h-,1.5 h-, 3 h-, 4.5 h-, 21 h-, 45 h-post-exercise. Oxylipins were measured with a targeted liquid chromatography-multiple reaction monitoring mass spectrometric method. RESULTS Significant time effects and substantial fold-increases (immediately post-exercise/pre-exercise) were measured for plasma levels of arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and 43 of 45 oxylipins. Significant interaction effects (4 trials x 8 time points) were found for plasma ARA (P<0.001) and DHA (P<0.001), but not EPA (P = 0.255), with higher post-exercise values found in the water trial compared to the carbohydrate trials. Significant interaction effects were also measured for 12 of 45 oxylipins. The data supported a strong exercise-induced increase in plasma levels of these oxylipins during the water trial, with carbohydrate ingestion (both bananas types and the sugar beverage) attenuating oxylipin increases, especially those (9 of 12) generated from the cytochrome P-450 (CYP) enzyme system. These trials differences were especially apparent within the first three hours of recovery from the 75-km cycling bout. CONCLUSIONS Prolonged and intensive exercise evoked a transient but robust increase in plasma levels of oxylipins, with a significant attenuation effect linked to acute carbohydrate ingestion for 28% of these, especially those generated through the CYP enzyme system. TRIAL REGISTRATION ClinicalTrials.gov, U.S. National Institutes of Health, NCT02994628.
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Combining a high DHA multi-nutrient supplement with aerobic exercise: Protocol for a randomised controlled study assessing mobility and cognitive function in older women.
Fairbairn, P, Tsofliou, F, Johnson, A, Dyall, SC
Prostaglandins, leukotrienes, and essential fatty acids. 2019;:21-30
Abstract
There is a complex interplay between cognition and gait in older people, with declines in gait speed coexisting with, or preceding cognitive decline. Omega-3 fatty acids, B vitamins, vitamin E, phosphatidylserine, and Ginkgo Biloba show promise in preserving mobility and cognitive function in older adults. Exercise benefits mobility and there is evidence suggesting positive interactions between exercise and omega-3 fatty acids on physical and cognitive function in older adults. Non-frail or pre-frail females aged ≥60 years are included in a randomized placebo controlled study. Intervention groups are: high DHA multi-nutrient supplement and exercise, placebo supplement and exercise, high DHA multi-nutrient supplement, and placebo supplement. Dietary supplementation is 24 weeks. The exercise intervention, two cycle ergometer classes per week, is for the final 12 weeks. The primary outcome is habitual walking speed, secondary outcomes include gait variables under single and dual task, five times sit to stand, verbal and spatial memory, executive function, interference control and health related quality of life. Blood fatty acids, serum homocysteine, dietary intake, physical activity, and verbal intelligence are measured to assess compliance and control for confounding factors. The study is registered at www.clinicaltrials.gov (NCT03228550).
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A Randomized Trial of Maternal Docosahexaenoic Acid Supplementation to Reduce Inflammation in Extremely Preterm Infants.
Valentine, CJ, Dingess, KA, Kleiman, J, Morrow, AL, Rogers, LK
Journal of pediatric gastroenterology and nutrition. 2019;(3):388-392
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Abstract
Maternal supplementation with 1000 mg/day docosahexaenoic acid (DHA) provides third trimester DHA accretion levels in breast milk for the preterm infant. We hypothesized that DHA supplementation to mothers providing breastmilk for extremely preterm infants would result in decreased inflammatory markers, in the infant. Mother/infant dyads (n = 27) were enrolled at birth and mothers were assigned to receive 200 or 1000 mg/day of DHA. Milk and plasma samples were analyzed for fatty acids and inflammatory markers. Decreases in inflammation were observed in both maternal and infant plasma and correlated with red blood cell (RBC) DHA levels. The fact that maternal DHA supplementation decreases infant markers of inflammation implies that DHA, delivered through breastmilk, has the potential to decrease inflammation in the infant.
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Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities.
Ulu, A, Sahoo, PK, Yuil-Valdes, AG, Mukherjee, M, Van Ormer, M, Muthuraj, PG, Thompson, M, Anderson Berry, A, Hanson, CK, Natarajan, SK, et al
International journal of molecular sciences. 2019;(18)
Abstract
Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue.
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Using joint models to disentangle intervention effect types and baseline confounding: an application within an intervention study in prodromal Alzheimer's disease with Fortasyn Connect.
van Oudenhoven, FM, Swinkels, SHN, Hartmann, T, Soininen, H, van Hees, AMJ, Rizopoulos, D
BMC medical research methodology. 2019;(1):163
Abstract
BACKGROUND Many prodromal Alzheimer's disease trials collect two types of data: the time until clinical diagnosis of dementia and longitudinal patient information. These data are often analysed separately, although they are strongly associated. By combining the longitudinal and survival data into a single statistical model, joint models can account for the dependencies between the two types of data. METHODS We illustrate the major steps in a joint modelling approach, motivated by data from a prodromal Alzheimer's disease study: the LipiDiDiet trial. RESULTS By using joint models we are able to disentangle baseline confounding from the intervention effect and moreover, to investigate the association between longitudinal patient information and the time until clinical dementia diagnosis. CONCLUSIONS Joint models provide a valuable tool in the statistical analysis of clinical studies with longitudinal and survival data, such as in prodromal Alzheimer's disease trials, and have several added values compared to separate analyses.
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Prenatal maternal docosahexaenoic acid intake and infant information processing at 4.5mo and 9mo: A longitudinal study.
Rees, A, Sirois, S, Wearden, A
PloS one. 2019;(2):e0210984
Abstract
Previous research suggesting an association between maternal prenatal docosahexaenoic acid (DHA) intake and infant cognition has yet to assess whether there is a critical trimester for the observed effects. We used a comprehensive Food Frequency Questionnaire to estimate DHA levels during both the second and third trimesters of pregnancy, in a sample of 125 pregnant women. Infants were assessed at 4.5 months and 9 months post-partum using specific tests of visual acuity, habituation, and visual attention. Based on maternal DHA levels during pregnancy, mothers were subdivided into high, medium, and low groups, and their infants compared for task performance using one-way ANOVAs with maternal DHA groups. On the 9 month visual acuity test, infants whose mothers were in the medium DHA group performed significantly better than those with mothers in the low or high DHA groups (p = 0.008). However, no significant finding was found for any of the other cognitive assessment measures. Despite a number of studies reporting a positive effect of higher DHA levels on cognitive development, this study fails to support those conclusions. We can, however, conclude that it appears to be DHA intake in the third trimester specifically, which is influencing the development of visual acuity towards the end of the first postnatal year.